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Using Truvada (tenofovir DF/emtricitabine) for
HIV prevention does not lower levels of feminising hormones, offering
reassurance for transgender women who are concerned about drug interactions,
according to a presentation at the 22nd International AIDS Conference (AIDS 2018) in Amsterdam.

Tenofovir levels in the blood were
reduced by 13% in trans women who used estradiol, but remained above the level
shown to confer protection, Akarin Hiransuthikul of the Thai Red Cross AIDS
Research Centre said during a press briefing
yesterday.

Some prior studies have shown
that blood concentrations of PrEP (pre-exposure prophylaxis) drugs in trans women were lower than
expected. This could occur either because feminising hormones interact in a way
that reduces drug levels or because trans women have poorer adherence. The latter
may occur because trans women are worried that PrEP could affect their hormone
therapy, which they prioritise over HIV prevention, Hiransuthikul said.

An analysis of data from the
pivotal iPrEx trial showed that Truvada
PrEP appears to work well for transgender women, but only if they
use it consistently. Studies of cisgender (non-trans) women suggest that they
may need to take PrEP more consistently than men to achieve a similar level of
protection.

Hiransuthikul and colleagues conducted a
pharmacokinetic study of potential drug-drug interactions between feminising
hormone therapy and PrEP. The iFACT study enrolled 20 HIV-negative trans women
who still had intact testicles and had not received injectable hormones within
the past six months. They were in their early- to mid-twenties and had normal body
weight and kidney function.

At the start of the study, the
participants started a feminising hormone therapy regimen
of estradiol valerate (2 mg/day), a form of the female hormone oestrogen, plus
the androgen blocker cyproterone acetate (25 mg/day). Hiransuthikul
stressed that feminising hormone regimens vary in different countries and these
results are only applicable to this particular regimen.

At week 3, the women started taking
Truvada. At week 5, they stopped the hormone regimen so the researchers could
compare PrEP drug levels on and off hormones, resuming at week 8. They then
continued on both hormones and PrEP through week 15.

The study showed that concurrent use of
hormone therapy and PrEP did not affect hormone levels. Comparing levels at
week 3 (before starting PrEP) and week 5 (while on PrEP), the researchers saw
no significant differences in maximum estradiol levels, estradiol levels 24
hours after dosing, estradiol half-life (how long it lasts in the body) or area
under the curve, a measure of total drug exposure over 24 hours. They also saw no changes in testosterone concentrations. They therefore
concluded that PrEP did not significantly affect levels
of feminising hormones.

However, looking at the effect of feminising
hormones on tenofovir, they found that tenofovir levels at 24 hours after dosing
and tenofovir total exposure was about 13% lower in the presence of estradiol. The
study did not measure emtricitabine levels.

This difference was statistically
significant, but Hiransuthikul emphasised that its clinical
implications for PrEP efficacy are not clear. Even with this reduction, the
mean tenofovir level was still above the target level shown to confer
protection in previous studies. He also noted that it is not known whether this
difference in blood levels correlates with tenofovir levels in rectal tissue,
where HIV exposure typically occurs.

"These results provide reassurance that you
can use PrEP without fear that it will decrease hormones to a suboptimal
level," Hiransuthikul concluded.

Truvada pharmacology

In a related study, Mackenzie Cottrell of the University of
North Carolina Eshelman School of Pharmacy and
colleagues compared tenofovir DF/emtricitabine pharmacology
in HIV-positive transgender and cisgender women on suppressive antiretroviral
therapy.

As background, Cottrell noted that trans women on feminising
hormone therapy maintain estradiol levels 2- to 9-fold higher than those
of cisgender women during the mid-follicular phase of the menstrual cycle and
up to 25-fold higher than those of cisgender men.

Estradiol
is known to increase the activity of nucleotidase enzymes, which could decrease
the active form of tenofovir – known as tenofovir diphosphate or TFVdp – while
increasing a competing nucleotide known as deoxyadenosine
triphosphate or dATP.

The
analysis included four transgender and four cisgender women. The trans women
had a median age of 42 years. The cisgender women were older, as the study
selected postmenopausal women to avoid confounding from hormone level
variations over the course of the menstrual cycle. Feminising hormone therapy
consisted of oral or injectable estradiol, medroxyprogesterone
and spironolactone. Median estradiol levels were 193 pg/ml in the trans women
and 13 pg/ml in the cisgender women.

The researchers measured levels of
TFVdp and dATP, and the ratio between them, as well as emtricitabine triphosphate (FTCtp) and its
competing nucleotide dCTP, in blood, peripheral blood mononuclear cells (PBMCs)
and rectal tissue samples. The study showed no differences in drug metabolite levels in the blood
plasma or PBMCs, so the report focused on rectal tissue levels.

There, the TFVdp:dATP ratio was about 8-fold lower
in transgender women compared with cisgender women, Cottrell reported. That is,
the level of TFVdp relative to dATP was significantly lower in trans women and
decreased as estradiol levels increased. One of the trans women had a ratio
below the EC90, the target concentration considered to be 90% effective.
However, lower TFVdp:dATP ratios were not associated with higher levels of HIV
RNA or DNA in rectal tissue, indicating that they did not compromise viral
suppression.

Emtricitabine ratios did not differ between the groups and were above
the EC90 target for all participants.

Asked about the implications of these findings,
Cottrell said we still need
more data on HIV-negative trans women taking antiretrovirals for HIV prevention
to see if they might be at risk during periods of lower adherence.

Studies
show that PrEP taken four times a week – and perhaps even less often – is
effective for cisgender men who have sex with men. However, until more data are
available, "it's fair to share with trans women that there are still
uncertainties and it might be better to take it daily," Cottrell
recommended.

NAM's news coverage of the 22nd International AIDS Conference has been supported by Gilead Sciences Europe Ltd. and ViiV Healthcare.

Official conference partners

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

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NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member
of your healthcare team for advice tailored to your situation.